Reactions

It is important to note that a carboxylic acid does not react directly with an amine to give an amide under mild conditions, mixing the two simply gives an ammonium carboxylate salt via acid-base reaction. This is why the carboxylic acid must be activated as a reactive acylating agent, converting the poor HO^- leaving group into a better one. The reactivity order of carboxylic acid derivatives is acyl chloride > anhydride > active ester.

Regardless of the activation method, the amide bond formation always proceeds via the same fundamental mechanism. First, the amine must be in its free base form to act as a nucleophile. A non-nucleophilic base such as diisopropylethylamine (DIPEA), N-methylmorpholine (NMM) or triethylamine (TEA) is therefore added to maintain this form and neutralize any acid generated during the reaction. The amine then attacks the electrophilic carbonyl carbon of the acylating agent, forming a tetrahedral intermediate. This intermediate subsequently collapses with the departure of the leaving group. Finally, the nitrogen is deprotonated by the base or, if sufficiently basic, by the leaving group anion itself, yielding the amide.